7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs useful in the treatment of thrombotic and vasospastic disease

ABSTRACT

7-Oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs are provided which are thromboxane A 2  (TXA 2 ) receptor antagonists or combined thromboxane A 2  receptor antagonist/thromboxane synthetase inhibitors and have the structural formula ##STR1## wherein R is SO 3  H, P(O)OR 3  OH or P(O)R 4  OH, X is O or NH, and Z, R 1 , R 2 , R 3  and R 4  are as defined herein.

DESCRIPTION OF THE INVENTION

The present invention relates to 7-oxabicycloheptyl substitutedheterocyclic amide prostaglandin analogs which are thromboxane A₂ (TXA₂)receptor antagonists or combined thromboxane A₂ receptorantagonist/thromboxane synthetase inhibitors useful, for example, in thetreatment of thrombotic and/or vasospastic disease, and have goodduration of action. These compounds have the structural formula I##STR2## and including all stereoisomers thereof, wherein

m is 1, 2 or 3; n is 1, 2, 3 or 4;

Z is ----(CH₂)₂ --, --CH═CH-- or ##STR3##

R is SO₃ H, P(O)OR³ OH or P(O)R⁴ OH;

X is O or NH;

R¹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aralkyl,aryl, cycloalkyl, or cycloalkylalkyl;

R² is hydrogen, lower alkyl, aryl, or aralkyl; or

R¹ and R² together with the nitrogen to which they are linked may form a5- to 8- membered ring;

R³ is H or lower alkyl; and

R⁴ is lower alkyl.

Thus, the compounds of the invention include the following types ofcompounds: ##STR4## wherein formulae IC and ID, Z¹ is --CH═CH-- or--(CH₂)₂ --.

Preferred are compounds of formula Ix ##STR5## where R is SO₃ H and R³is cycloalkylalkyl, m is 1 and n is 2 or 3.

The term "lower alkyl" or "alkyl" as employed herein includes bothstraight and branched chain radicals of up to 20 carbons, preferably 1to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1, 2 or 3 halo substituents, an aryl substituent, analkyl-aryl substituent, a haloaryl substituent, a cycloalkylsubstituent, an alkylcycloalkyl substituent, hydroxy or a carboxysubstituent.

The term "cycloalkyl" includes saturated cyclic hydrocarbon groupscontaining 3 to 12 carbons, preferably 3 to 8 carbons, which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may besubstituted with substituents such as halogen, lower alkyl, alkoxyand/or hydroxy groups.

The term "aryl" or "Ar" as employed herein refers to monocyclic orbicyclic aromatic groups containing from 6 to 10 carbons in the ringportion, such as phenyl or naphthyl. Aryl (or Ar), phenyl or naphthylmay include substituted aryl, substituted phenyl or substitutednaphthyl, which may include 1 or 2 substituents on either the phenyl ornaphthyl such as lower alkyl, trifluoromethyl, halogen (Cl, Br, I or F),lower alkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl,alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl.

The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used hereinrefers to lower alkyl groups as discussed above having an arylsubstituent, such as benzyl.

The term "lower alkoxy", "alkoxy" or "aralkoxy" includes any of theabove lower alkyl, alkyl or aralkyl groups linked to an oxygen atom.

The term "halogen" or "halo" as used herein refers to chlorine, bromine,fluorine or iodine with chlorine being preferred.

The term "lower alkenyl" or "alkenyl" as employed herein with respect tothe R¹ substituent includes a carbon chain of up to 16 carbons,preferably 3 to 10 carbons, containing one double bond which will beseparated from "N" by at least one saturated carbon moiety such as--(CH₂)_(q) -- where q can be 1 to 14, such as 2-propenyl, 2-butenyl,3-butenyl, 2-pentenyl, 4-pentenyl and the like, and may include ahalogen substituent such as I, Cl, or F.

The term "lower alkynyl" or "alkynyl" as employed herein with respect tothe R¹ substituent includes a carbon chain of up to 16 carbons,preferably 3 to 10 carbons, containing one triple bond which will beseparated from "N" by at least one saturated carbon moiety such as--(CH₂)_(q') -- where q' can be 1 to 14, such as 2-propynyl, 2-butynyl,3-butynyl and the like.

The compounds of formula I of the invention may be prepared as follows.

The various compounds of the invention where R is SO₃ H may be preparedstarting with ester V ##STR6## which is subjected to reduction bytreating with a reducing agent such as lithium borohydride or sodiumborohydride, in the presence of an inert organic solvent such astetrahydrofuran, diethyl ether or dioxane to form the alcohol VI##STR7##

Alcohol VI is made to undergo an activation reaction wherein alcohol VIis treated with an activating agent such as methanesulfonylchloride inthe presence of an organic base such as triethylamine, pyridine ordiisopropylethylamine and an inert organic solvent such as methylenechloride, chloroform or tetrahydrofuran, to form the activated compoundVII ##STR8## (wherein Q is an activating group).

The activated compound VII is then made to undergo a displacementreaction wherein VII is treated with potassium thioacetate or otheralkali metal thioester such as sodium thioacetate, in the presence of aninert solvent such as dimethylsulfoxide or dimethylformamide, to formthe thioester VIII ##STR9##

The thioester VIII is then oxidized, for example, by treatment withoxone in the presence of water and acetone, to form the compound of theinvention IF ##STR10##

The compounds of formula I of the invention wherein R is --P(O)OR³ OHmay be prepared starting with alcohol VI which is made to undergo anactivation reaction wherein alcohol VI is treated with an activator suchas triphenyl phosphine dibromide in an inert solvent, such aschloroform, methylene chloride, or carbon tetrachloride to form thebromide IX ##STR11##

Bromide IX is then subjected to a displacement reaction wherein bromideIX is treated with a trialkyl phosphite such as trimethyl phosphite[(CH₃ O)₃ P] or triethyl phosphite [(C₂ H₅ O)₃ P] using thetrialkylphosphite as solvent at elevated temperatures of from about 100°C. to about 155° C. for about 2 to about 20 hours to form thephosphonate diester X ##STR12##

The phosphonate diester X is then hydrolyzed by treatment with an alkalimetal hydroxide such as lithium hydroxide or sodium hydroxide to formthe phosphonic acid compound of the invention having the structure IG##STR13##

In an alternative procedure, compounds of the invention IF may beprepared by treatment of bromide IX with an alkali metal sulfite such asNa₂ SO₃ in a suitable solvent such as water or tetrahydrofuran-water, attemperatures of from about 25° C. to about 100° C., followed byacidification with, for example, 1N HCl to form IF.

The compounds of formula I of the invention wherein R is --P(O)OR³ OHand R³ is H may be prepared from phosphonate diester X by treatment withtrimethylsilyl bromide, trimethylsilyl iodide, or trimethylsilylchloride/sodium iodide in an inert solvent such as methylene chloride oracetonitrile at a temperature of about 0° C. to about 30° C. to form thephosphonic acid IH ##STR14##

The compounds of formula I of the invention wherein R is --P(O)R⁴ OH maybe prepared using the procedure outlined for the conversion of bromideIX to acid IG except substituting R⁴ --P(Oalkyl)₂ for P(Oalkyl)₃ to formphosphinic acid IJ. ##STR15##

The starting esters V may be prepared as disclosed in European PatentApplication No. 0374952 and European Patent Application No. 0391652which correspond to U.S. application Ser. No. 540,026 filed Jun. 18,1990, now U.S. Pat. No. 5,100,889, which is incorporated herein byreference.

The compounds of this invention have four centers of asymmetry asindicated by the asterisks in formula I. However, it will be apparentthat each of the formulae set out above which do not include asterisksstill represent all of the possible stereoisomers thereof. All of thevarious stereoisomeric forms are within the scope of the invention.

The various stereoisomeric forms of the compounds of the invention,namely, cis-exo, cis-endo and all trans forms and stereoisomeric pairsmay be prepared by employing starting materials and following theprocedures as outlined in U.S. Pat. No. 4,143,054. Examples of suchstereoisomers are set out below. ##STR16##

The nucleus in each of the compounds of the invention is depicted as##STR17## for matter of convenience; it will also be appreciated thatthe nucleus in the compounds of the invention may be depicted as##STR18##

The compounds of this invention are thromboxane receptor antagonists andas such are useful as inhibitors of thromboxane receptor mediatedactions. The term "thromboxane receptor antagonist" includes compoundswhich are so-called thromboxane A₂ receptor antagonists, thromboxane A₂antagonists, thromboxane A₂ /prostaglandin endoperoxide antagonists,TP-receptor antagonists, or thromboxane antagonists.

The compounds of the invention are also thromboxane synthetaseinhibitors and thus are useful as inhibitors of thromboxane production.

The compounds of this invention are useful as inhibitors of plateletfunction, i.e., for the prevention and treatment of thrombotic vascularocclusive disorders, whether complete or partial, for example, arterialthrombosis, including that of the coronary, cerebral, ophthalmic,hepatic, mesenteric, renal, peripheral arteries or vascular or organgrafts, unstable angina, transient ischemic attacks, or intermittentclaudication. They may be useful to prevent thrombosis followingvascular injury produced in the course of diagnostic or therapeuticprocedures such as endarterectomy or angiography. The compounds may beuseful in the treatment or prevention of disorders characterized byplatelet consumption and/or activation, including, platelet activation,dysfunction, and/or loss during extracorporeal circulation, the use ofradiographic contrast agents, thrombotic thrombocytopenia purpura,disseminated intravascular coagulation, purpura fulminans, hemolytictransfusion reaction, or hemolytic uremic syndrome, systemic lupus,cyclosporine-induced renal toxicity, pulmonary hypertension, sideeffects from dialysis, or abdominal aortic aneurism repair. Thecompounds may be used in the treatment of venous thrombosis or embolism,including pulmonary embolism, deep venous thrombosis, hepatic veinthrombosis, and renal vein thrombosis.

The compounds of this invention are useful as inhibitors of arterial orvenous vasoconstriction. Accordingly, they may be useful to preventvasoconstriction associated with unstable angina, chronic stable angina,and variant, or Prinzmetal's angina, Raynaud's syndrome, migraineheadache, vasospasm of the coronary, cerebral, ophthalmic, hepatic,mesenteric, renal, peripheral arteries or vascular grafts, vascularinjury such as that associated with surgery or trauma. Hypertension ofpregnancy, the hepato-renal syndrome, and pulmonary hypertension areadditional examples of vasoconstrictive disorders treatable by thecompounds of this invention.

The compounds of this invention are useful as inhibitors ofbronchoconstriction, i.e., airway hyperresponsiveness, allergicbronchospasm, asthma, and bronchoconstrictive responses toenvironmental, infectious, noxious or mechanical stimuli.

The compounds of this invention are useful as inhibitors of ischemic andreperfusion injury to various tissues, including, myocardium, skin,brain, bowel, or kidney, alone or in combination with other agentsintended to restore blood flow. For example, these compounds may beuseful for improving postischemic myocardial function and decreasingmyocardial infarct size. Ischemia caused by reduced blood flow duringdiagnostic or therapeutic procedures may benefit by treatment with thesecompounds, for example, they reduce the myocardial stunning observedafter bypass surgery. In addition, they may be useful for reducing thetissue injury caused by a stroke.

The compounds of this invention may be useful in the prevention ortreatment of other conditions including burns, diabetic retinopathy,tumor metastases and tardive dyskinesia. The compounds may be useful inpotentiating diuretic-induced diuresis.

In addition, the thromboxane receptor antagonists of the invention maybe used with a thrombolytic agent such as t-PA, streptokinase,urokinase, prourokinase or anisoylated plasminogenstreptokinaseactivator complex (APSAC) within 6 hours of a myocardial infarction. Insuch case, the thrombolytic agent may be used in amounts conventionallyemployed, for example, as disclosed in the Physicians' Desk Referencefor reducing post-ischemic myocardial injury.

The compounds of the invention can be administered orally orparenterally to various mammalian species known to be subject to suchmaladies, e.g., humans, cats, dogs and the like in an effective amountwithin the dosage range of about 0.1 to about 100 mg/kg, preferablyabout 0.2 to about 50 mg/kg (or from about 1 to about 2500 mg,preferably from about 5 to about 2000 mg) on a regimen in single or 2 to4 divided daily doses.

The active substance can be utilized in a composition such as tablet,capsule, solution or suspension containing about 5 to about 500 mg perunit of dosage of a compound or mixture of compounds of formula I or intopical form for wound healing (0.01 to 5% by weight compound of formulaI, 1 to 5 treatments per day). They may be compounded in conventionalmatter with a physiologically acceptable vehicle or carrier, excipient,binder, preservative, stabilizer, flavor, etc., or with a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene) ascalled for by accepted pharmaceutical practice. Also as indicated in thediscussion above, certain members additionally serve as intermediatesfor other members of the group.

The compounds of the invention may also be administered topically totreat peripheral vascular diseases and as such may be formulated as acream or ointment.

The following Examples represent preferred embodiments of the presentinvention. Unless otherwise indicated, all temperatures are expressed indegrees Centigrade.

EXAMPLE 1[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzeneethanesulfonicAcid A.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneethanoicAcid, Methyl Ester

The title ester was prepared as described in Example 81, Parts A to K ofU.S. application Ser. No. 540,026, now U.S. Pat. No. 5,100,889 andEuropean Patent Application 0391652.

B.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzeneethanol

To a stirred mixture of Part A ester (170 mg, 0.34 mmol) in 4 mL of dryTHF under argon at room temperature was added LiBH₄ (247 mg, 11.2 mmol).The mixture was stirred at room temperature for 24 hours and acidifiedto pH 1 by the addition of 1N HCl solution. The mixture was diluted with20 mL of water and extracted with dichloromethane (4×30 mL). Thecombined dichloromethane extracts were washed with 1N HCl solution (1×20mL) and brine (1×40 mL). The organic layer was dried (MgSO₄), filteredand concentrated in vacuo. This was chromatographed on 24 g of Mercksilica gel 60 using 2% CH₃ OH/CH₂ Cl₂ as eluant to give 73 mg (45%) oftitle alcohol.

TLC: silica gel, 2% CH₃ OH/CH₂ Cl₂, R_(f) 0.22, I₂.

C.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneethanol,Methanesulfonate Ester

To a stirred mixture of Part B alcohol (70 mg, 0.15 mmol), andtriethylamine (Et₃ N) (0.03 mL, 0.22 mmol) in 5 mL of drydichloromethane was added methanesulfonyl chloride (MsCl) (15.0 μL, 0.19mmol). The mixture was stirred at room temperature for 110 minutes anddiluted with 40 mL of dichloromethane. The mixture was washed with 1NHCl solution (2×10 mL), saturated NaHCO₃ solution (1×10 mL) and brine(1×10 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo to give 81 mg of title mesylate in quantitativeyield.

TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) 0.64, I₂.

D.[1S-(1α,2α,3α,4α)]-2-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneethanethiol,Acetate Ester

To a stirred mixture of Part C mesylate (81.4 mg, 0.15 mmol) in 1.5 mLof dimethylsulfoxide (DMSO) was added potassium thioacetate (33.0 mg,0.29 mmol). The mixture was stirred at room temperature for 5 hours anddiluted with 100 mL of ether. The mixture was washed with saturatedNaHCO₃ solution (2×15 mL). The organic layer was dried (MgSO₄), filteredand concentrated in vacuo. Purification was effected by flashchromatography on 10 g of Merck silica gel 60 using 1% CH₃ OH/CH₂ Cl₂ aseluant to give 62.7 mg (80%) of title thioacetate.

TLC: silica gel, 2% CH₃ OH/CH₂ Cl₂, R_(f) 0.78, Ce(SO₄)₂.

E.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneethanesulfonicAcid

To a stirred mixture of Part D thioacetate (60 mg, 0.12 mmol) in 4 mL ofmethanol and 2 mL of acetone was added an aqueous oxone solution (2 mL,preparation was described in Example 2). The mixture was stirred at roomtemperature for 63 hours and concentrated in vacuo. The residue wasdiluted with 5 mL of 1N HCl solution, saturated with NaCl and extractedwith ethyl acetate (EtOAc) (4×20 mL). The combined EtOAc extracts werewashed once with 15 mL of brine, dried (MgSO₄), filtered andconcentrated in vacuo to give title sulfonic acid (55.6 mg, 92%).

TLC: silica gel, 1% acetic acid (HOAc) in 10% CH₃ OH/CH₂ Cl₂, R_(f)0.14, Ce(SO₄)₂.

EXAMPLE 2[1S-(1α,2α,3α,4α)]-3-[[3-4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanesulfonicAcid A.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanol

The title compound was prepared as described in Example 1, Parts A to Nof U.S. application Ser. No. 540,026 and European Patent Application391652.

B.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanol,Methanesulfonate Ester

To a stirred mixture of Part A alcohol (88.2 mg, 0.18 mmol) and Et₃ N(37.0 μL, 0.27 mmol) in 3 mL of dry dichloromethane was addedmethanesulfonyl chloride (MsCl) (18.0 μL, 0.23 mmol). The mixture wasstirred at room temperature for 1 hour and diluted with 40 mL ofdichloromethane. The mixture was washed with 1N HCl solution (2×10 mL)and saturated NaHCO₃ solution (1×10 mL). The organic layer was dried(MgSO₄), filtered and concentrated in vacuo to give 102 mg of titlemesylate in quantitative yield.

TLC: silica gel, 2% CH₃ OH/CH₂ Cl₂, R_(f) 0.46, I₂.

C.[1S-(1α,2α,3α,4α)]-2-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanethiol,Acetate Ester

To a stirred mixture of Part B mesylate (102 mg, 0.18 mmol) in 3 mL ofdry DMSO under argon was added potassium thioacetate (40.7 mg, 0.36mmol). The mixture was heated at 90° C. for 70 minutes and cooled toroom temperature. The mixture was diluted with 150 mL of ether andwashed with saturated NaHCO₃ solution (3×30 mL) and brine (1×30 mL). Theether layer was dried (MgSO₄), filtered and concentrated in vacuo. Thiswas chromatographed on 10 g of Merck silica gel 60 using 1% CH₃ OH/CH₂Cl₂ as eluant to give 87.1 mg (88%) of title thioacetate.

TLC: silica gel, 2% CH₃ OH/CH₂ Cl₂, R_(f) 0.78, Ce(SO₄)₂.

D.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanesulfonicAcid

To a stirred mixture of Part C thioacetate (40 mg, 0.07 mmol) in 4 mL ofmethanol and 2 mL of acetone was added an aqueous oxone solution (1.5 mLof a solution of 15 g of oxone dissolved in 50 mL of water). Thismixture was then diluted with 50 mL of methanol. The resultingprecipitate was filtered off and the filtrate was concentrated in vacuoto about 20 mL. The mixture was diluted with water to 50 mL and used asis. The mixture was stirred at room temperature for 76 hours andconcentrated in vacuo. The residue was diluted with 4 mL of 1N HClsolution, saturated with NaCl and extracted with EtOAc (4×10 mL). Thecombined EtOAc extracts were washed once with 10 mL of brine, dried(MgSO₄), filtered and concentrated in vacuo to give title sulfonic acid(43 mg, 88%). TLC: silica gel, 1% HOAc in 10% CH₃ OH/CH₂ Cl₂ , R_(f)0.14, Ce(SO₄)₂.

EXAMPLE 3 1S-(1α,2α,3α,4α)]-[2-2-3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenyl]ethyl]phosphonicAcid, Methyl Ester A. [1S-(1α,2α,3α,4α)]-2-[2-[[3-4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenyl]ethylBromide

To a stirred solution of 1 mmol of triphenylphosphine in 10 mL oftoluene at 0° C. is added 1 mmol of bromide. The resultant slurry isstirred for 15 minutes at which time a solution of 1 mmol of Example 1,Part B alcohol and 1 mmol pyridine in toluene is added. The reactionmixture is stirred for 2 hours at 0° C. and then is isolated byextractive work-up to give the crude bromide which is purified by silicagel chromatography using hexanes/ethyl acetate as eluant to afford titlebromide.

B.[1S-(1α,2α,3α,4α)]-[2-[2-[[3-[4-[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenyl]ethyl]phosphonicAcid, Dimethyl Ester

A mixture of 10 mmol of Part A bromide and 10 mmol of trimethylphosphite are stirred and heated to 130° C. for 1 hour. The crudeproduct is purified by silica gel chromatography using CH₃ OH/CH₂ Cl₂mixtures to afford the title phosphonate.

C.[1S-(1α,2α,3α,4α)]-[2-[2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]phenyl]ethyl]phosphonicAcid, Methyl Ester

To a solution of 1 mmol of Part B phosphonate in 10 mL of CH₃ OH isadded 2.0 mL of 1N NaOH solution. This mixture is stirred at 23° C. for6 hours and then is concentrated in vacuo. The residue is diluted with 5mL of 1N HCl and 5 mL of water and extracted with ethyl acetate. Theorganic layers are dried (MgSO₄), filtered and concentrated in vacuo toafford title compound.

EXAMPLE 4[1S-(1α,2α,3α,4α)]-[2-[2-[[3-[4-[[(4-Cyclohexylbutyl)amino)]carbonyl]-2-oxazolyl]-7-oxabicyclo-2.2.1]hept-2-yl]methyl]phenyl]ethyl]phosphonicAcid

To a stirred solution of 1 mmol of Example 3, Part B phosphonate and 2mmol of chlorotrimethylsilane in 1.0 mL of acetonitrile is added 2.0mmol of sodium iodide. The reaction mixture is stirred for 15 minutesand the resultant precipitate is removed by filtration. The filtrate isconcentrated in vacuo and then is treated with water. The aqueoussolution is concentrated in vacuo to afford the title compound.

EXAMPLE 4A1S-(1α,2α,3α,4α)]-[2-[2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-2.2.1]hept-2-yl]methyl]phenyl]ethyl]methylphosphinicAcid A.[1S-(1α,2α,3α,4α)]-[2-[2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenyl]ethyl]methylphosphinicAcid, Methyl Ester

A mixture of 10 mmol of Example 3, Part A bromide and 10 mmol of methyldimethylphosphite is stirred at 130° C. for 1 hour. The crude product ispurified by silica gel chromatography using hexane/ethyl acetate toafford the title compound.

B.[1S-(1α,2α,3α,4α)]-[2-[2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenyl]ethyl]methylphosphinicAcid

To a stirred solution of 1 mmol of Part A phosphinate in 10 mL of CH₃ OHis added 2 mL of 1N NaOH solution. The reaction mixture is stirred for 6hours and then is concentrated in vacuo. The residue is diluted with 5mL 1N HCl and 5 mL H₂ O and then is extracted with ethyl acetate. Theorganic extracts are dried (MgSO₄), filtered and concentrated in vacuoto afford the title compound.

Following the procedures of Examples 1 to 4a and U.S. application Ser.No. 540,026 filed Jun. 18, 1990, the following compounds within thescope of the present invention may be prepared.

    __________________________________________________________________________     ##STR19##                                                                    Example                                                                            (CH.sub.2).sub.m                                                                  (CH.sub.2).sub.n                                                     No.  m   n   Z    X  R.sup.1       R.sup.2                                                                            R                                     __________________________________________________________________________     5   1   2   CHCH O  C.sub.6 H.sub.13                                                                            CH.sub.3                                                                           SO.sub.3 H                             6   2   2   CHCH O                                                                                 ##STR20##    C.sub.2 H.sub.5                                                                    P(O)(CH.sub.3)OH                       7   3   1   (CH.sub.2).sub.2                                                                   NH                                                                                ##STR21##    i-C.sub.3 H.sub.7                                                                  P(O)(OCH.sub.3)OH                      8   1   2   (CH.sub.2).sub.2                                                                   O                                                                                 ##STR22##    H    SO.sub.3 H                             9   1   2   (CH.sub.2).sub.2                                                                   O  i-C.sub. 3 H.sub.7                                                                          H    P(O)(OCH.sub.3)OH                     10   1   3   CHCH O                                                                                 ##STR23##    n-C.sub.4 H.sub.9                                                                  SO.sub.3 H                            11   1   2   CHCH O                                                                                 ##STR24##    H    SO.sub.3 H                            12   1   2   CHCH O                                                                                 ##STR25##    CH.sub.3                                                                           P(O)(C.sub.3 H.sub.7)OH               13   1   2   (CH.sub.2).sub.2                                                                   O                                                                                 ##STR26##    H    SO.sub.3 H                            14   1   2   CHCH NH                                                                                ##STR27##    H    P(O)(OC.sub.3 H.sub.7)OH              15   2   2   (CH.sub.2).sub.2                                                                   O                                                                                 ##STR28##    CH.sub.2 C.sub.6 H.sub.5                                                           P(O)(OC.sub.2 H.sub.5)OH              16   1   2   CHCH O  C.sub.2 H.sub.5                                                                             H    SO.sub.3 H                            17   1   3   CHCH NH                                                                                ##STR29##    C.sub.2 H.sub.5                                                                    P(O)(OH).sub.2                        18   1   2   (CH.sub.2).sub.2                                                                   O  (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                            CH.sub.3                                                                           SO.sub. 3 H                           19   1   3   CHCH O  n-C.sub.3 H.sub.7                                                                           CH.sub.2 C.sub.6 H.sub.5                                                           P(O)(OC.sub.2 H.sub.5)OH              20   1   2   CHCH NH n-C.sub.5 H.sub.11                                                                          H    SO.sub.3 H                            21   2   3   CHCH O                                                                                 ##STR30##    CH.sub.3                                                                           P(O)(OCH.sub.3)OH                     22   1   2   CHCH O                                                                                 ##STR31##         SO.sub.3 H                            23   1   2   CHCH N                                                                                 ##STR32##    H    P(O)(OH).sub.2                        24   2   2   (CH.sub.2).sub.2                                                                   O                                                                                 ##STR33##    H    P(O)(C.sub.2 H.sub.5)OH               25   2   3   CHCH O  C.sub.6 H.sub.5                                                                             C.sub.6 H.sub.5                                                                    P(O)(C.sub.2 H.sub.5)OH               26   1   2   CHCH NH CH.sub.2 C.sub.6 H.sub.5                                                                    CH.sub.2 C.sub.6 H.sub.5                                                           P(O)(OC.sub.2 H.sub.5)OH              __________________________________________________________________________     ##STR34##                                                                    Ex. No.                                                                             m  n   X  (position)                                                                         R.sup.2                                                                           R         R.sup.1                                    __________________________________________________________________________    27    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        CH.sub.3                                                         28    1  2   O                                                                (2)   H  P(O)OCH.sub.3 OH                                                                  4-OH-phenylbutyl                                                 29    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        propyl                                                           30    1  2   O                                                                (2)   H  P(O)(C.sub.2 H.sub.5)OH                                                           pentyl                                                           31    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexylethyl                                                  32    1  2   O                                                                (2)   H  P(O)(OCH.sub.3)OH                                                                 t-butylbutyl                                                     33    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        4-methoxyphenylbutyl                                             34    1  2   O                                                                (2)   H  P(O)(C.sub.3 H.sub.7)OH                                                           4-cyclohexylbuten-2-yl                                           35    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        5-cyclohexylpenten-4-yl                                          36    1  2   O                                                                (2)   H  P(O)(OC.sub.3 H.sub.7)OH                                                          heptyl                                                           37    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexyl                                                       38    1  2   O                                                                (2)   H  P(O)(OC.sub.2 H.sub.5)OH                                                          isopropyl                                                        39    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexyloctyl                                                  40    1  2   N                                                                (2)   H  SO.sub.3 H                                                                        4-phenylbutyl                                                    41    1  2   N                                                                (2)   H  P(O)(OCH.sub.3)OH                                                                 4-phenylbutyl                                                    42    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        phenyl                                                           43    1  2   O                                                                (2)   H  P(O)(OCH.sub.3)OH                                                                 p-biphenyl                                                       44    1  2   N                                                                (2)   H  SO.sub.3 H                                                                        4-phenylbutyl                                                    45    1  2   O                                                                (2)   H  P(O)(OH).sub.2                                                                    4-benzyloxyphenyl                                                46    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        4-hydroxyphenyl                                                  47    1  2   O                                                                (2)   H  P(O)(OCH.sub.3)OH                                                                 3-iodo-propen-2-yl                                               48    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        4-(m-OH, o-iodophenyl)butyl                                      49    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        4-cyclohexylphenyl                                               50    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        p-methoxyphenyl                                                  51    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        p-chlorophenyl                                                   52    1  2   O                                                                (2)   H  P(O)(CH.sub.3)OH                                                                  p-chlorophenyl                                                   53    1  2   O                                                                (2)   H  P(O)(OC.sub.2 H.sub.5)OH                                                          p-chlorophenethyl                                                54    1  2   N                                                                (2)   H  SO.sub.3 H                                                                        t-butyl                                                          55    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        1,1-dimethylpropyl                                               56    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        n-C.sub.18 H.sub.37                                              57    1  2   O                                                                (2)   H  P(O)(OH).sub.2                                                                    benzyl                                                           58    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        5-hydroxy-5-methyl hexyl                                         59    1  2   O                                                                (2)   H  P(O)(OH).sub.2                                                                    5-carboxy-5-methyl hexyl                                         60    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        H                                                                61    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        p-F-phenylbutyl                                                  62    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        C.sub.10 C.sub.21                                                63    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        2,2-dimethylbutyl                                                64    1  2   O                                                                (2)   H  P(O)(OCH.sub.3)OH                                                                 2,2-dimethypropyl                                                65    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        3,3-dimethylbutyl                                                66    1  2   O                                                                (2)   H  P(O)(OCH.sub.3)OH                                                                 2-(4-fluorophenyl)ethyl                                          67    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        2-phenylethyl                                                    68    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexylbutyl                                                  69    1  2   O                                                                (2)   H  P(O)(OCH.sub.3)OH                                                                 cyclohexylbutyl                                                  70    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexylpropyl                                                 71    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexyl                                                       72    1  2   O                                                                (2)   CH.sub.3                                                                         SO.sub.3 H                                                                        pentyl                                                           73    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexylpentyl                                                 74    1  2   O                                                                (2)   CH.sub.3                                                                         SO.sub.3 H                                                                        cyclohexylbutyl                                                  75    2  1   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexylbutyl                                                  76    2  1   O                                                                (3)   H  SO.sub.3 H                                                                        cyclohexylbutyl                                                  77    2  2   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexylbutyl                                                  78    1  3   O                                                                (2)   H  P(O)(OCH.sub.3)OH                                                                 cyclohexylbutyl                                                  79    1  1   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexylbutyl                                                  80    2  3   O                                                                (3)   H  SO.sub.3 H                                                                        cyclohexylbutyl                                                  81    1  2   N                                                                (2)   H  SO.sub.3 H                                                                        cyclohexylbutyl                                                  82    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        cyclohexylbutyl                                                  83    1  2   O                                                                (2)   H  SO.sub.3 H                                                                        6-heptynyl                                                       __________________________________________________________________________

What is claimed is:
 1. A compound having the formula ##STR35## includingall stereoisomers thereof, wherein m is 1, 2 or 3;n is 1, 2, 3 or 4; Zis --(CH₂)₂ --, --CH═CH-- or ##STR36## R is SO₃ H; X is O; R¹ ishydrogen, alkyl, lower alkenyl containing 3 to 16 carbons, lower alkynylhaving 3 to 16 carbons, phenyl, naphthyl, phenylalkyl, naphthylalkyl,cycloalkyl, or cycloalkylalkyl; R² is hydrogen, lower alkyl, aryl, oraralkyl; R³ is H or lower alkyl; and R⁴ is lower alkyl; the term "alkyl"or "lower alkyl" as employed herein alone or as part of another grouprefers to a radical having 1 to 20 carbons and the term "cycloalkyl" asemployed herein alone or as part of another group refers to a radicalhaving 3 to 12 carbons.
 2. The compound as defined in claim 1 wherein mis 1 and n is 2 or
 3. 3. The compound as defined in claim 1 wherein R¹is cycloalkylalkyl.
 4. The compound as defined in claim 1 wherein Z is##STR37##
 5. The compound as defined in claim 1 wherein Z is ##STR38##6. The compound as defined in claim 1 wherein X is O, R¹ iscycloalkylalkyl, m is 1, n is 2 or 3 and Z is ##STR39##
 7. The compoundas defined in claim 6 wherein R is SO₃ H.
 8. The compound as defined inclaim 1 which is[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-cyclohexylbutyl)amino]butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicsulfonic acid.
 9. The compound as defined in claim 1 which is[1S-(1α,2α,3α,4α)]-3-[[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneethanesulfonicacid.
 10. A method of inhibiting platelet aggregation andbronchoconstriction, which comprises administering to the circulatorysystem of a mammalian host a therapeutically effective amount of acompound as defined in claim
 1. 11. A composition for inhibitingplatelet aggregation and bronchoconstriction comprising atherapeutically effective amount of a compound as defined in claim 1,and a pharmaceutically acceptable carrier therefor.
 12. A method ofinhibiting platelet aggregation which comprises administering to amammalian host a therapeutically effective amount of a compound asdefined in claim
 1. 13. A method of inhibiting bronchoconstrictionassociated with asthma, which comprises administering to a mammalianhost a therapeutically effective amount of a compound as defined inclaim
 1. 14. A method for improving post-ischemic myocardial function,which comprises administering to a mammalian host in need of suchtreatment a therapeutically effective amount of a compound as defined inclaim 1.